Extended release compositions comprising as active compound venlafaxine hydrochloride

ABSTRACT

The present invention relates to an extended release composition comprising as active compound Venlafaxine Hydrochloride, in which Venlafaxine Hydrochloride is coated on a non pareil inert core, which coated core is then coated with polymeric layer which enables the controlled release of the Venlafaxine Hydrochloride.

The present invention relates to extended release compositions comprising as active compound Venlafaxine Hydrochloride.

Venlafaxine Hydrochloride is an antidepressant having formula 1

being designated (R/S)-1-[2-(dinehylamino)-1-(4-methoxyphenyl)ethy1]cyclohexanol hydrochloride or (±)-1-[a](dimethylamino)methyl]p-methoxybenzyl cyclohexanol hydrochloride, having the empirical formula of C17H27NO2 hydrochloride and molecular weight of 313.87.

Venlafaxine hydrochloride is a white to off white crystalline solid with a solubility of 572 mg/ml in water (adjustment to ionic strength of 0.2 M with sodium chloride). Its octanol: water (0.2 M sodium chloride) partition coefficient 0.43. Effexor XR the Brand product is formulated as an extended release capsule for once a day oral administration.

The drug release has so far been controlled by diffusion through the coating membrane on the spheroids and is not pH dependent. Known capsules containing Venlafaxine Hydrochloride comprise amounts equivalent to 37.5 mg, 75 mg, or 150 mg of Venlafaxine. The inactive ingredients are mainly cellulose, ethylcellulose, gelatin, hydroxypropyl methylcellulose, iron oxide, and titanium dioxide.

Controlled or extended release dosage forms of medicament are conventionally produced as hydrogel matrix based tablets. At this technology the controlled release dosage forms are simply prepared by mixing the active material with the appropriate rate of controlling polymers and then that mixture is compressed into the desired controlled release tablets. The rate controlling polymers are normally termed as hydrogels. Examples of such polymers are cellulose ethers such as ethyl cellulose or hydroxypropylcellulose. Patents describing preparation methods of such dosage forms are described for example in U.S. Pat. No. 4,966,768 or U.S. Pat. No. 4,389,393.

In some cases, for example with very water soluble active materials and with relatively high doses it is not feasible to produce tablets which enable appropriate control on the drugs release. This is the case, for example with Venlafaxine Hydrochloride.

In such a case a suitable approach is encapsulating the drug and producing extended release capsules dosage forms. When preparation of such dosage forms is considered, the preferred way is to mix the active ingredient with at least one binding agent to form a uniform mixture which is later moistended with water or with an appropriate organic solvent to form an extrudable plastic mass, from which small particles, cylinders shape (1 mm diameter) of drug/matrix are extruded, chopped into appropriate lengths and converted to spheroids using spheronization equipment. These spheroids are further dried and than film coated with an appropriate polymer to form a film with the desired release patterns. The most widely used excipient in the extruding process is microcrystalline cellulose in its different grades usually water is used for the wetting process.

Polymers widely used for coating are ethyl cellulose or Eudragit (Ammonio methacrylate copolymer, type A or B). Water soluble ingredients are normally mixed with the ethyl cellulose or with other hydrophobic polymers, such as pore forming agents to assist the control on the drugs release through the hydrophobic coating layer. The water soluble ingredients such as hydroxypropyl cellulose or polyethylene glycol may serve as plasticizers as well.

Venlafaxine Hydrochloride has so far been formulated into a controlled release dosage form with the ability to provide in a single dose a therapeutic blood serum level of the drug over a twenty four hour period. By this method, tighter plasma therapeutic range control can be obtained and a multiple dosing is avoided in this manner. The sharp peaks and troughs in blood plasma drug levels are avoided as well.

With the conventional release dosage forms of Venlafaxine Hydrochloride (tablets), peak blood plasma levels appeared after 2-4 hrs, in contrast to the extended release dosage forms, when plasma levels of Venlafaxine Hydrochloride rose after administration for between five to eight hrs (average—6) and than begin to fall through a protracted, substantially linear decrease from the peak plasma level for the reminder of the period, maintaining therapeutic level of the drug during the entire twenty four hours period.

In WO 99/22724 (AHP, Sherman) a detailed description of preparating an encapsulated dosage form (coated spheroids) of Venlafaxine Hydrochloride is provided. By the method described therein, a spheroid core is prepared by extruding and spheronizing a mixture of the drug with microcrystalline cellulose, and than coating it with an ethyl cellulose hydroxypropylcellulose mixture.

This dosage form provides an extended release product with the following in vitro dissolution specifications: Average % venlafaxine Time (hrs) HCL release 2 <30 4 30-55 8 55-80 12 65-90 24 >80

These dissolution characteristics are pH, RPM independent.

In the present invention an alternative once daily bioequivalent formulation to the innovators one (Effexor XR, described in WO 99/22724) has been developed.

As already mentioned, with high dose water soluble product such as Venlafaxine Hydrochloride (150 mg), the usual preferred way of encapsulating it is by preparing and coating an appropriate beads, using the extrusion spheronization process.

In the present invention the microencapsulation has been changed, i.e. is being performed by layering the drug over an inert pareil core, and than coating it with an appropriate polymeric mixture.

The present invention thus consists in an extended release composition comprising as active compound Venlafaxine Hydrochloride, in which Venlafaxine Hydrochloride is coated on a non pareil inert core, which coated core is then coated with a polymeric layer which enables the controlled release of the Venlafaxine Hydrochloride.

The composition preferably comprises 30-60% of Venlafaxine Hydrochloride per weight of the total dosage form.

In a preferred embodiment of the present invention, the Venlafaxine Hydrochloride is suitably connected to a binder, said binder may be e.g. polyvinyl pyrrolidone (povidone), hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. The composition preferably comprises 0.5%-10% of the binder per weight of the total dosage form.

Advantageously the non pareil inert core is an inert sugar core, a microcrystalline cellulose or the like. The composition preferably comprises 30-60% of the core per weight of the total dosage form.

Alternatively the drug might be sprayed as it is and the water is then used as binding enhancement agent.

Advantageously the coated core is coated with an isolating/protecting/separating layer, which layer is suitably composed of polymers such as polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystallinecellulose, carrageenan, GMS etc. The composition preferably comprises 0.5-10% of the isolating layer per weight of the total dosage form.

The core or the isolating layer is coated then with an additional polymeric layer which enables the controlled release of Venlafaxine Hydrochloride. Said additional polymeric layer is composed, e.g. of a hydrophobic polymer mixed with an appropriate hydrophobic or hydrophilic plasticizer. Said polymeric layer is suitably sprayed over the coated non pareil layer or over the isolating layer.

Appropriate coating polymers are, e.g. Eudragit, cellulose derivatives such as hydroxypropylmethylcellulose, ethyl cellulose, cellulose acetate, etc. Their suitable plasticizers are, e.g. castor oil, dibutyl sebacate, glyceryl monostearate, diethyl phtalate, glyceryl trihepthanoate, triethyl citrate, etc.

The coating polymeric layer may also be a wax based coating.

The composition preferrably comprises 2-15% of the hydrophobic polymer per weight of the total dosage form; and preferably 0.1-2% per weight of the hydrophobic plasticizer per weight of the total dosage form.

The above processes are conventional processes that may be performed in a fluid bed coater with a bottom spraying mechanism.

In the composition according to the present invention, preferably not more than 40% of the drug are released after two hours, not more than 60% released after 4 hours and not more than 80% after 8 hours.

The compositions obtained are suitably, e.g. filled into hard gelatin capsules or compressed into tablets.

This formulation has an identical in vitro dissolution profile as Effexor XR (see Sherman, WO99/22724). They are not sensitive to any changes in dissolution conditions. It is bioequivalent to Effexor XR 150 mg caps.

The coating process being used to produce the composition according to the present invention is more efficient than the method being used at the Sherman patent. Moreover, it enables the preparation of the drug in a single type of equipment, e.g. a fluid bed coater.

The present invention will now be illustrated with reference to the following examples without being limited by them.

The process preparing the composition according to the present invention is suitably performed as follows (all temperatures are given in degrees centigrade):

-   -   a. When Venlafaxine Hydrochloride is connected to a binder the         Venlafaxine Hydrochloride is connected to the binder by methods         know per se.     -   b. Stage 1         -   Coating the non pareil core with the Venlafaxine             Hydrochloride (advantageously connected with a binder) is             performed at an inlet temperature of 45°-55° (preferably at             50°) at an outlet temperature of 35°-45° (preferably at             40°).         -   At the end of the spraying process, the composition is dried             for 10 minutes without nozzle with 30 cfm air flow.     -   c. Stage 2         -   The coated core obtained in Stage 1 is coated with the             insulating layer at an inlet temperature of 60°±3° at an             outlet temperature of 50°±2.     -   d. Stage 3 (when an insulating layer is present in Stage 2)         -   The core is coated with a further preliminary layer, the             conditions of said coating are:         -   Inlet temp: −50°±2         -   Outlet temp: −40°±5

EXAMPLE NO. 1 Without Binder

Stage 1: Components—Non pareils 25/30 150 gr

-   -   Venlafaxine Hydrochloride 37.5 gr     -   H2O 150 gr.

Stage 2: Components—150 gr layered pellets from stage 1

-   -   Ethocel 45cp—15 gr     -   Methocel 5cp—1 gr     -   Ethanol BP 300 gr

At the end of the spray process the composition for 10 minutes without nozzle with 30 cfm.

EXAMPLE NO. 2

Stage 1: components—Non pareils (inert sugar pellets) 150 gr

-   -   Povidone K-30—3.3 gr.     -   Venlafaxine Hydrochloride—165 gr.     -   Ethanol BP—670 gr.

Stage 2: components—150 gr. layered pellets from stage 1

-   -   Ethocel 45 cp.—15 gr     -   Methocel 5 cp—1 gr     -   Ethanol BP—300 gr

The coating process was performed in a “4” fluid bed coater made by Coating Place Inc. USA.

EXAMPLE NO. 3

Stage 1: components—Non pareils 25/30—150 gr

-   -   Venlafaxine Hydrochloride 37.5 gr     -   Povidone K-30—0.75 gr     -   Ethanol BP—160 gr

Stage 2: components—150 gr layered pellets from stage 1

-   -   Eudragit RS 30 D—150 gr     -   Triethyl citrate—9gr     -   Glycerol monostearate—2.25gr     -   Polysorbate 80—1 gr     -   Water—140 gr

The coating process was performed in a “4” fluid bed coater, made by Coating Place Inc. USA.

EXAMPLE NO. 4

Stage 1: components—Non-pareils 25/30—150 gr.

-   -   Povidone K-30—0.75 gr.     -   Venlafaxine HCL—37.5 gr.     -   Ethanol BP—160 gr.

Stage 2: components—150 gr. pellets from stage 1.

-   -   Eudragit RS 30D—150 gr.     -   Eudragit RL 30D—15 gr.     -   Triethyl citrate—9 gr.     -   Glycerol monostearate—2.25 gr.     -   Polysorbate 80—1 gr     -   Water—140 gr.

All processes were performed in a “4” fluid bed coater, made by Coating Place Inc. USA.

EXAMPLE NO. 5

Stage 1: components—150 gr. Non pareils 25/30

-   -   Povidene K-90—4.5 gr.     -   Venlafaxine HCL—150 gr.     -   Ethanol BP—670 gr.     -   Water—110 gr

Stage 2: components—150 gr. Pellets from stage 1

-   -   Povidone K-30—3.75 gr.     -   Ethanol absolute—60 gr.

Stage 3: components—Pellets from stage 2

-   -   Ethocel 100 cp.—8 gr.     -   Dibutyl sebacate—0.8 gr.     -   Ethanol absolute—300 gr. 

1. An extended release composition comprising as active compound Venlafaxine Hydrochhloride, in which Venlaxfaxine Hydrochloride is coated on a non pareil inert core, which coated core is then coated with a polymeric layer which enables the controlled release of the Venlaxfaxine Hydrochloride.
 2. A composition according to claim 1, wherein the composition comprises 30-60% of Venlaxfaxine Hydrochloride per weight of the total dosage form.
 3. A composition according to 1, wherein the Venlaxfaxine Hydrochloride is suitably connected to a binder.
 4. A composition according to claim 3, wherein the binder is selected from the group consisting of polyvinyl pyrrolidone hydroxypropylcellulose and hydroxypropylmethylcellulose.
 5. A composition according to claim 4, wherein the composition comprises 0.5%-10% of the binder per weight of the total dosage form.
 6. A composition according to claim 5, wherein the non pareil inert core is an inert sugar core or a microcrystalline cellulose core.
 7. A composition according to claim 6, which comprises 30-60% of the core per weight of the total dosage form.
 8. A composition according to claim 7, wherein the core is coated with an isolating/protecting/separating layer.
 9. A composition according to claim 8, wherein the isolating layer is composed of at least one polymer selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline, cellulose, carrageenan, and GMS.
 10. A composition according to claim 9, wherein the isolating layer comprises 0.5-10% of the weight of the total dosage form.
 11. A composition according to claim 10, being coated with an additional polymeric layer.
 12. A composition according to claim 11, wherein said additional polymeric layer is composed of a hydrophobic polymer mixed with an appropriate hydrophobic or hydrophilic plasticizer.
 13. A composition according to claim 12, wherein said coating polymer selected from the group consisting of Eudragit and a cellulose derivative, said plasticizer is selected from the group consisting of castor oil, dibutyl sebacate, glyceryl monostearate, diethyl phalate, glyceryl trihepthanoate, and triethyl citrate.
 14. A composition according to claim 13, which comprises 2-15% of the hydrophobic polymer per weight of the total dosage form; and 0.1-2% per weight of the hydrophobic plasticizer per weight of the total dosage form.
 15. A composition according to 2, wherein the Venlaxfaxine Hydrochloride is suitably mixed with a binder.
 16. A composition according to claim 15, wherein the binder is selected from the group consisting of polyvinyl pyrrolidone, hydroxypropylcellulose and hydroxypropylmethylcellulose.
 17. A composition according to claim 16, wherein the composition comprises 0.5%-10% of the binder per weight of the total dosage form.
 18. A composition according to claim 3, wherein the composition comprises 0.5%-10% of the binder per weight of the total dosage form.
 19. A composition according to claim 1, wherein the non pareil inert core comprises inert sugar or microcrystalline cellulose.
 20. A composition according to claim 1, which comprises 30-60% of the core per weight of the total dosage form.
 21. A composition according to claim 1, wherein the core is coated with a layer providing at least one function of isolating, protecting and separating.
 22. A composition according to claim 21, wherein the layer providing at least one function of isolating, protecting and separating is composed of a polymer selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline, cellulose, carrageenan, and GMS.
 23. A composition according to claim 8, wherein the isolating layer comprises 0.5-10% of the weight of the total dosage form.
 24. A composition according to claim 1, coated with an additional polymeric layer.
 25. A composition according to claim 24, wherein said additional polymeric layer is composed of a hydrophobic polymer mixed with an appropriate hydrophobic or hydrophilic plasticizer.
 26. A composition according to claim 25, wherein said hydrophobic polymer is Eudragit or a cellulose derivative, and said plasticizer is selected from the group consisting of castor oil, dibutyl sebacate, glyceryl monostearate, diethyl phalate, glyceryl trihepthanoate, and triethyl citrate.
 27. A composition according to claim 26, which comprises 2-15% of the hydrophobic polymer per weight of the total dosage form; and 0.1-2% per weight of the hydrophobic plasticizer per weight of the total dosage form.
 28. A composition according to claim 12, which comprises 2-15% of the hydrophobic polymer per weight of the total dosage form; and 0.1-2% per weight of the hydrophobic plasticizer per weight of the total dosage form. 